HIV-induced sensory neuropathy (HIV-SN) is a major global health problem as 35 million people are infected with HIV and a considerable percentage of these will develop neuropathy. HIV-SN poses a major burden on the quality of life of affected patients as many suffer from neuropathic pain that is resistant to antiretroviral therapy as well a other drugs commonly used to treat neuropathic pain. Despite the pressing need for novel therapeutics, the development of new treatment strategies has been hampered by our lack of understanding of the mechanisms underlying HIV-induced neuropathy. Using an SIV/macaque model of HIV-neuropathy that closely recapitulates HIV-induced damage, we propose to investigate the underlying cause of HIV-SN by 1) developing tools that allow the use of corneal confocal microscopy to non-invasively track the development of peripheral neuropathy and 2) measuring levels of SIV-induced inflammatory mediators in plasma and dorsal root ganglia. In this macaque model, we will also record neuronal activity from unmyelinated nociceptive afferents in peripheral nerves to investigate whether such afferents develop signs of peripheral sensitization after infection as sensitization could contribute to spontaneous pain and hyperalgesia seen in patients with HIV-SN. In addition to peripheral nociceptive nerve fibers, nociceptive neurons in DRG may be damaged by inflammatory mediators produced locally in DRG or present in the circulation. Using the patch-clamp electrophysiology technique, we will investigate whether nociceptive DRG neurons develop hyperexcitability during SIV infection and whether inflammatory mediator-sensitive voltage-gated sodium channel isoforms play a role. By correlating the findings obtained with the different techniques, we will obtain a better understanding of the mechanisms underlying HIV-sensory neuropathy to develop new strategies for treatment.